Corticotropin-releasing hormone (CRH or CRF) is the major hypothalamic regulator of ACTH release. Our previous studies showed that peripheral CRH and its family members Urocortin 2 (Ucn2) and Urocortin 3 (Ucn3) participate in intestinal inflammation by binding to CRH receptor 2 (CRHR2) and activating important pathways linked to mucosal healing following colitis and IBD, including cell proliferation, and migration and wound healing. This application will test the novel hypothesis that CRHR2 activation coordinates mucosal healing following colitis by interacting with colonic epithelial cells and colonic fibroblats to stimulate proliferation, enhance epithelial wound healing, inhibit apoptosis and stimulate release of cytokines and growth factors from human colonic fibroblasts. The role of the functional CRHR2 isoforms, CRHR2?, CRHR2?, and its recently characterized soluble mouse slice variant, sCRHR2? will also be examined. The following aims will address these hypotheses. Aim 1 will establish the role of CRHR2 and its ligands CRH, Ucn2 and Ucn3 in mucosal healing following colitis using specific CRHR2 receptor antagonists, CRHR2 -/- and intestinal epithelial cell specific CRHR2-/- (CRHR2LoxP/LoxP) mice. Aim 2 will examine the hypothesis that CRHR2 activation stimulates mucosal healing re-programming and investigate the underlying signaling pathways involved, with particular focus on the IL-6/STAT3, Akt and EGFR pathways on human colonic epithelial cells. Aim 3 will address the role of CRHR2 signaling on human colonic fibroblasts in mucosal healing using colonic fibroblasts isolated from CRHR2-/- and intestinal epithelial cell specific CRHR2-/- mice as well as human intestinal fibroblasts isolated from IBD patients. These studies should advance our understanding on the pathogenesis of IBD and define the role and mechanisms of CRH signaling in this important group of diseases.